Updates on Paediatric HIVDCH 2018

Dr James NuttallPaediatric Infectious Diseases Unit

Red Cross War Memorial Children’s Hospital & University of Cape Townjames.nuttall@uct.ac.za

HIV exposure & infection

• HIV exposure– An infant born to a mother with HIV infection and indicated by the presence of HIV antibodies

in blood of a child <18 months of age

– Ingestion of breastmilk from a woman with HIV infection (HIV antibodies in blood of infant may be absent)

– Exposure to certain other body fluids of an HIV-infected person (e.g. following sexual abuse)

• “Seroreversion”

– Absence of HIV antibodies in a child known to be HIV exposed

• HIV infection

– <18 months of age: PCR or viral load (x2 )

– ≥18 months of age: antibody tests (rapid tests, x2)

• HIV exposed uninfected (HEU)

– PCR negative HIV exposed child

– Seroreversion

WHO Clinical Staging for Paediatric HIV InfectionStage One

• Asymptomatic• Persistent generalized

lymphadenopathy (PGL)

WHO Clinical Staging for Paediatric HIV Infection

Stage Two

• Unexplained persistent hepatosplenomegaly• Papular pruritic eruptions• Extensive wart virus infection • Extensive molluscum contagiosum• Recurrent oral ulcerations • Unexplained persistent parotid enlargement • Lineal gingival erythema • Herpes zoster• Recurrent / chronic URTI (otitis media, sinusitis, otorrhoea) • Fungal nail infections

WHO Clinical Stage 2 conditions

WHO Clinical Staging for Paediatric HIV Infection

Stage Three

• Unexplained moderate malnutrition (60 - 80% EWFA) not responding adequately to standard therapy

• Unexplained persistent diarrhoea (≥14 days)

• Unexplained persistent fever (>1month)

• Persistent oral candidiasis (after first 6 weeks of life)

• Oral hairy leukoplakia

• Acute necrotizing ulcerative gingivitis / periodontitis

• Lymph node TB• Pulmonary TB• Severe recurrent presumed

bacterial pneumonia (≥2 episodes in 6 months)

• Symptomatic lymphoid interstitial pneumonitis (LIP)

• Chronic HIV-associated lung disease incl. bronchiectasis

• Unexplained anaemia (<8g/dl), neutropaenia (<500/mm3) or thrombocytopenia (<50,000/ mm3) for > 1 month

WHO Clinical Stage 3 conditions

WHO Clinical Staging for Paediatric HIV InfectionStage four• Unexplained severe malnutrition

(< 60% EWFA)• Pneumocystis pneumonia• Recurrent severe presumed

bacterial infections (excl. pneumonia)

• Chronic herpes simplex infection (>1 month duration)

• Extrapulmonary TB• Kaposi's sarcoma• Oesophageal candidiasis• CNS toxoplasmosis outside

neonatal period • HIV encephalopathy• CMV infection (retinitis or

another organ outside neonatal period)

• Extrapulmonary cryptococcosis incl. meningitis

• Any disseminated endemic mycosis

• Chronic cryptosporidiosis or Isosporiasis (with diarrhoea > 1 month)

• Disseminated non-tuberculous mycobacterial infection

• Cerebral or B cell non-Hodgkin lymphoma

• Progressive multifocal leukoencephalopathy (PML)

• HIV-associated cardiomyopathy or nephropathy

• Acquired HIV-associated rectovaginal fistula

WHO Clinical Stage 4 conditions

Antiretrovirals

• Entry and Fusion inhibitors

• Nucleoside (NRTI) & nucleotide (NtRTI)reverse transcriptase inhibitors– abacavir, lamivudine, zidovudine, tenofovir

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)– Efavirenz, nevirapine, etravirine

• Integrase inhibitors– Raltegravir, dolutegravir

• Protease inhibitors (PIs)– Lopinavir/ritonavir, atazanavir/ritonavir, darunavir/ritonavir

National guidelines, April 2015

W Cape guidelines, October 2018

Steps to starting ART in Children

• Confirm HIV diagnosis & provide counseling

• Assess and manage opportunistic illnesses & malnutrition if present

• Social criteria for starting ART: identification of reliable caregiver

• Further counseling: treatment literacy & treatment readiness

• Baseline investigations

• Appropriate drug regimen (protocols)

Social requirements for ART

Mandatory:• a reliable, responsible adult to at least administer medication

Desirable:• Treatment “ready” i.e. clinic attendance, adequate counselling and demonstration

of medication.• Able to travel to and attend ARV centre monthly and without difficulty• Disclosure to household or friend

Certainly advisable…• “Assistant caregiver” identified and included in work-up• “Back-up” plan in case of crisis• Know maternal CD4 count and assess general health. Refer or treat if indicated

1st line ART regimens for children& adolescents (SA NDOH 2015)

• Infants and children <3yrs or <10kg:– Abacavir (ABC) + Lamivudine (3TC) + Lopinavir/ritonavir

(LPV/r, Kaletra)• Neonates (<4 weeks of age): avoid LPV/r (Kaletra)

• Children ≥3yrs (& ≥10kg) & early adolescents (<15yrs & <40kg):– Abacavir (ABC) + Lamivudine (3TC) + Efavirenz (EFV)

• Children ≥3 years and exposed to Nevirapine (NVP) for 6 weeks or longer (PMTCT) should be initiated on ABC + 3TC + LPV/r

• Late adolescents (≥15yrs & ≥40kg):– Tenofovir (TDF) + Emtricitabine (FTC) (or Lamivudine (3TC))

+ Efavirenz (EFV)

Baseline investigations at HIV diagnosis & before starting ART(Infants, children, early adolescents)

Prior to initiation of ART PurposeFull blood count If <8 g/dl start ART & discuss with specialist

CD4 count (if not done in last 6 mths) Baseline assessment

Cholesterol & triglycerides if on PI regimen Baseline assessment

ALT (if jaundiced or on TB Rx) To assess for liver dysfunction

Neurocognitive developmental assessment With appropriate available tool

At initial diagnosis of HIV PurposeConfirm HIV status Requires 2 x HIV PCR tests in children <18 months of age and 2 x HIV rapid

tests or ELISA tests in children >18 months of age

Document weight, height, head circumference (<2 yrs) & development

To monitor growth & development & identify eligibility for ART

Screen for TB symptoms To identify HIV/TB co-infection

WHO clinical staging (≥5 yrs) To determine if patient is eligible for ART

CD4 count Baseline assessment

FBC & differential white cell count To detect anaemia, neutropaenia, thrombocytopaenia

Neurocognitive developmental assessment With appropriate available tool

Baseline investigations at HIV diagnosis(Late adolescents 15-19 yrs)

At initial diagnosis of HIV PurposeConfirm HIV status

Baseline CD4 count & WHO clinical staging To assess eligibility for ART (CD4<500), fast-tracking (CD4<200 / stage 4), prioritisation (CD4 <350), Co-trimoxazole prophylaxis (CD4<200), CrAg/CLAT testing (CD4<100)

Screen for pregnancy Pregnant women eligible for ART. Conception counselling

Screen for TB symptoms To identify HIV/TB co-infection

Mantoux test Assess need for IPT

Screen for STIs & syphilis For treatment & counselling

Assessment of major non-communicable diseases

To identify concomitant chronic disease

Screen for hepatitis B To identify HIV/HBV co-infection & eligibility for ART

Weight and height in adolescents To determine appropriate ART regimen

Baseline investigations before starting ART(Late adolescents 15-19 yrs)

Prior to initiation of ART PurposeCrAg / CLAT if baseline CD4 <100 To identify patients who require treatment or

prophylaxis for cryptococcal meningitis

Serum creatinine for clients starting on Tenofovir

To detect renal insufficiency (calculate creatinine clearance)

Hb & differential white cell count for clients starting on Zidovudine

To detect anaemia / neutropaenia: do not useAZT if Hb ≤8)

Cholesterol & triglycerides if on PI regimen

Baseline assessment

ALT if client starting on Nevirapine To assess for liver dysfunction

Fasting cholesterol and triglycerides for clients starting on Lopinavir/ritonavir

To identify clients with contraindications to LPV/r or at risk of LPV/r related hyperlipidaemia. If total cholesterol >6 mmol/l or triglycerides >5 mmol/l, consider using Atazanvir/r instead of LPV/r

Staying on ART

Four main aspects requiring on-going monitoring are:

–Adherence & support – Treatment efficacy: clinical, CD4, viral load–Drug toxicity and adverse events–Developmental and psychosocial progress

Assessment & support of caregivers

• Pre-ART– Screening form– 3 counselling sessions– Home visit if necessary– Child support grants– Secondary caregiver

(treatment partner)– Practical demonstration of

ARV drug regimen

• On ART – Interview with caregivers– Return of medications / pill

counts & demonstration– Support groups– Assistance with disclosure– Referral of mother / father /

siblings for HIV testing / care / ART

– Referral to community-based services where possible

Return of medication at each clinic visit

• Provides a focus for the consultation (doctor, nurse, counsellor)

• Demonstrate dosing procedures• Pill counts• Problems• Drug side-effects• Avoids wastage and accumulation of half-

used bottles at home (re-issue)

ART demonstration kit to teach caregivers

Pillbox & pill counter

Monitoring treatment efficacy on ART(Infants, children, early adolescents, late adolescents)

On ART PurposeHeight, weight, head circumference (<2years) and development

To monitor growth and developmental stage

Clinical assessment To monitor response to ART, and exclude adverse effects

CD4: ALL at mth 12, then1-5 years: 6 mthly> 5 years: If CD4 < 200 cells/mm3 repeat 6 mthly until two consecutive CD4’s > 200 cells/mm3

To monitor response to ART, stop co-trimoxazole prophylaxis as per national guidelines

VL: All: at mth 4 and 12, then- children <5 years: 6 mthly- children 5 years to 15 years: 12 mthly

To monitor viral suppression response to ARTTo identify treatment failure andproblems with adherence

Neurocognitive developmental assessments

With appropriate available tool

Monitoring toxicity on ART(Infants, children, early adolescents)

On ART PurposeHb and differential white cell count at month 1, 2, 3 and 6 months if on AZT

To identify Zidovudine-related haematological toxicity

Cholesterol & triglycerides at 1 year & then every 12 months if on PI-based regimen

To monitor for PI-related metabolic side-effects. Advise dietary modification & refer for appropriate management if hyperlipidaemia present

Monitoring toxicity on ART(Late adolescents)

On ART Purpose

Serum creatinine: at month 1, 4, 12 and then annually if on Tenofovir

To identify TDF toxicity, calculate creatinine clearance

ALT:• If on Nevirapine or Efavirenz and develops rash or

symptoms suggestive of hepatitis• If on TB treatment & LPV/r

To detect NVP or EFV toxicity

Weekly while while increasing from standard dose to double dose LPV/r, then monthly for duration of TB treatment

Hb and differential white cell count at month 1, 2, 3 and 6 months if on AZT

To identify Zidovudine-related haematological toxicity

Fasting cholesterol & triglycerides at month 3 on Lopinavir/ritonavir.Repeat annually if clinically indicated

To detect clients LPV/r toxicity. If total cholesterol >6 mmol/l or triglycerides >5 mmol/l, consider switch to Atazanvir/r. Management of hyperlipidaemia should include dietary modification and statins if indicated.

Hep B sAg To identify HBV co-infection in pts on TDF switching to 2nd line regimens so that TDF can be retained in the 2nd line regimen

ADVERSE REACTIONS TO ART

• Abacavir hypersensitivity reaction– ≥2 of:

• fever • rash• gastrointestinal symptoms (e.g. D+V, abdominal pain) • constitutional symptoms (e.g. fatigue, myalgia)• respiratory symptoms (e.g. dyspnoea, cough, pharyngitis)

– Symptoms worsen immediately after dose– Early consultation with health care provider– Avoid stopping therapy without consultation if possible. Also avoid

ongoing use / re-challenge as risk of mortality

• Lipodystrophy syndrome– Electively switch from stavudine or zidovudine to abacavir (or tenofovir in

older children/adolescents) in patients who are virally suppressed

2nd-line ART regimens

1st line regimen 2nd line regimen

PI-basedABC + 3TC + LPV/rd4T + 3TC + LPV/rUnboosted PI-based regimenRifampicin while on LPV/r

Consult with expert for advice

NNRTI-basedABC + 3TC + EFV (or NVP)d4T + 3TC + EFV (or NVP)

AZT + 3TC + LPV/rAZT + ABC + LPV/r

1st line regimen 2nd line regimenTDF-based regimen AZT + 3TC + LPV/rd4T-based regimen TDF + 3TC (or FTC) + LPV/r

Infants & children

Adolescents & adults

2nd line ART after PI-based 1st line1st line “3rd drug” 2nd line “3rd drug” Comment

LPV/rtv “Refer”

No standard

recommendation

Consider new

generation boosted PI

(DRV) +/or NNRTI (e.g.

etravirine) +/or

integrase inhibitor (e.g.

raltegravir)

Seek expert adviceand genotyping to inform choice of regimen. Avoid empirical use ofNNRTI + 2 NRTIs as may lead to rapid virological failure

• If LPV/r is 1st PI, virus usually remains susceptible to LPV even in setting of

treatment failure. Exceptions include co-treatment with rifampicin,

breaking/crushing of Aluvia tablets

• NRTI cross-resistance, 3TC resistance, and archived NNRTI resistance following

NVP exposure in PMTCT programme may impact on potency of 2nd line regimen

Van Zyl GU et al. Pediatr Infect Dis J 2009;28(12):1125-7

Taylor BS et al. AIDS Res Hum Retroviruses 2011;27:945-56

Frange P et al. Pediatr Infect Dis J. 2011

HIV/TB co-infection & treatment• Very common problem

– 29-66% of children on TB Rx at time of starting ART in SA studies (Meyers 2011, Rossouw 2015)

• First line ART regimen for children <3 yrs of age is LPV/r-based

• Rifampicin dramatically reduces plasma LPV concentrations predisposing patients on rifampicin-based TB treatment & LPV/r to treatment failure & LPV resistance

• For adult patients on a PI regimen, options include:– Boosting with additional ritonavir– Double-dose Aluvia– Rifabutin instead of rifampicin

HIV/TB co-infection

Treatment in children

• For young children (7mths-<4yrs) on LPV/r & rifampicin

only current option is boosting with additional ritonavir

(Ren, 2008)

• But poor palatability, short supply, short expiry period

• Double-dose LPV/r failed to maintain adequate lopinavir

exposure in children aged 6mths-2.5yrs (McIlleron, 2011)

• Rifabutin dosed at 5mg/kg 3 x/wk in 6 children <5yrs of age

on LPV/r

• failed to achieve PK targets equivalent to current adult dosing

recommendations (150mg daily)

• resulted in high rates of severe transient neutropenia (Moultrie, 2015)

HIV resistance in children

• Transmitted (primary)– Mother failing 1st / 2nd / 3rd line ART

• Antenatally• During breastfeeding

• Acquired– During PMTCT (NVP ± AZT for 6-12wks) – During ART (child failing 1st/ 2nd / 3rd line ART)

• NRTI/NNRTI/PI/II

Genotypic resistance testing:Important principles

• Only useful for detecting resistance to drugs currently being taken by patient (or within 4 weeks of stopping them)

• Helps to exclude drugs from a future regimen, may not indicate which drugs will work

• Viral load must be >1000 copies/ml & won’t detect resistance in minor variants (<20% of viral population)

• Interpretation may be difficult and requires expertise

• Expensive (±R2000): few guidelines on optimal use of resistance testing in large treatment programmes

Eligibility for genotypic resistance testing (SA NDOH, 2015)

• Failure on 2nd line ART regimen – HIV RNA >1000 copies/ml on 2nd line ART for >12-

18 mths despite adherence interventions

• Failure on 1st line PI-based ART regimen (children)– HIV RNA >1000 (if previous unboosted PI or

rifampicin-based TB treatment) or 30000 copies/ml on 1st line PI-based regimen despite adherence interventions

Eligibility for genotypic resistance testing (W Cape, 2015)

• Infants <2yrs of age who are newly diagnosed as HIV-positive if their mothers were exposed to PI-based ART during pregnancy or breastfeeding

• Patients on a PI regimen with ≥3 viral loads of ≥1000 at least 8-12 weeks apart after adherence has been addressed– Children (<15yrs) on PI regimen for ≥1 year– Adults on PI regimen for ≥2 yrs

• Requires motivation (incl. adherence assessment) & approval by committee

3rd line ART

Expert review committee manages access to 3rd

line ART– National / Provincial– Genotype-proven PI resistance is pre-requisite for

3rd line ART – 3rd line regimen based on genotype result, expert

opinion and supervised care– Darunavir/ritonavir, Raltegravir/Dolutegravir,

Etravirine

3rd line ARTARVs & formulations

• Darunavir (DRV)– Tablets: 75mg, 150mg, 600mg– Oral suspension (100mg/ml): unregistered, Sec 21/compassionate use access– DRV not approved for use <3yrs of age/<10kg

• Raltegravir– Tablets: 25mg/100mg (chewable), 400mg (film-coated), not interchangeable– Oral suspension (100mg powder for suspension): unregistered, Sec

21/compassionate use access– Not approved for children <4 weeks of age/<3kg

• Etravirine– Tablets: 100mg (registered), 25mg: unregistered, Sec 21/compassionate use

access– ETR not approved for children <6yrs of age

New ARVs & new uses for current ARVs

• Raltegravir– Role in PMTCT (maternal use during pregnancy)– Approved from 4 wks of age but consider use only in exceptional

circumstances (risk of resistance)– Role in 3rd line ART in combination with DRV/r

• Dolutegravir is awaited (currently approved for use in children >12 yrs of age)– Safety, pharmacokinetics & efficacy of dolutegravir in treatment-experienced

HIV-infected adolescents (IMPAACT P1093)*– Investigational dose in clinical trial in ART-experienced children <12yrs of age

• Atazanavir/r powder formulation approved from 3 mths/10kg, no approved dose of powder formulation for children >25kg unable to swallow tablets

*Viani, 2015

Neonatal ARTRationale

• Can we reduce both the early and late HIV-associated morbidity &

mortality by starting ART during the neonatal period?

• Identification of HIV infection by PCR testing at birth rather than at

6 weeks of age

• Preservation of capacity to respond to routine infant vaccines

(Penisieroso, PNAS 2009)

• Rapid control of HIV viraemia in infants can reduce size of HIV reservoir

(Persaud, 2012)

• Possibility of later structured ART interruption following very early ART

initiation (CHER study)?

• (HIV cure agenda…)

Early HIV-associated morbidity & mortality

• Children with HIV Early Antiretroviral Therapy Study (CHER),

(Violari, NEJM, 2008)

• HIV PCR testing at 4 weeks of age

• Randomised to early or deferred ART

• Median age at ART start in early arm was 7.4 wks

• Early ART reduced early infant mortality by 76% and HIV progression by 75%

compared to ART deferred until clinical or CD4 criteria were met

• 33% (10/30) deaths occurred in early ART arm

• Early severe HIV disease precedes early antiretroviral therapy in

infants: Are we too late? (Innes, JIAS 2014)

• Cohort of infants from Soweto & Cape Town

• Median age at ART start 8.4 wks (IQR 7.2-9.7)

• 62% (250/403) had advanced HIV disease at time of starting ART• Each month increase in age at ART initiation increased the odds of advanced

HIV disease at ART initiation (OR: 1.69, CI: 1.05-2.71)

HIV PCR testing at birth• Detection of intrauterine HIV transmission to

infant– Associated with rapid HIV disease progression– Very early (neonatal) ART initiation offers a window of

opportunity to prevent or reduce rapid disease progression

• ARV prophylaxis for HIV-exposed neonates– Single (NVP) or dual (AZT+NVP) ARV prophylaxis– Transition from ARV prophylaxis to ART (SA & US)– ART as prophylaxis and treatment if HIV-infected (UK)

Neonatal ARTWhat are the risks?

• Safety & efficacy of ART in neonatal population– PI vs NNRTI-based regimens– Uncertain dosing

• Neonatal pharmacokinetics & pharmacodynamics: immature physiological systems (renal, hepatic, GIT) – Premature neonates

• Co-morbidities in neonatal period– Congenital syphilis, TB, CMV

• Optimal transition from neonatal ARV prophylaxis to neonatal ART?– Maternal ART & neonatal ARV prophylaxis also complicates HIV

diagnosis in neonate

Are we able to recommend a safe and effective neonatal ART regimen…?

• “For neonates and for premature infants (until 42 weeks corrected gestational age), PK data are currently inadequate to formulate an effective complete ART regimen. Although dosing is available for zidovudine and lamivudine, data are inadequate for other classes of ART

• Providers considering treatment of infants <2 weeks or premature infants should contact a pediatric HIV expert for guidance because the decision about whether to treat and what to use will involve weighing the risks and benefits of using unapproved ART dosing, and incorporating case-specific factors such as exposure to ARV prophylaxis”

Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children.Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. March 2015

Neonatal ARTRegimen considerations

ABC/3TC/LPV/r• Safety / toxicity

– Abacavir• Dosing data lacking <3 mths of age• Toxicity not dose-dependent in older

infants – 3TC

• Dosing data is available• Haematological toxicity

– LPV/r (Kaletra®)• Dosing data is available • Serious toxicity reports

• Efficacy– Unknown in neonatal/early infancy

period– Superior to NVP-based regimens in

older children regardless of perinatal NVP exposure (P1060 study)

AZT/3TC/NVP• Safety / toxicity

– AZT• Dosing guidelines are available• Haematological toxicity

– 3TC– NVP

• Lack of dosing data for treatment• Potential hepatotoxicity

• Efficacy– NVP-based regimen may be inferior

to PI-based regimen particularly in NNRTI-exposed neonates

– Transitional regimen

Neonatal ARTGaps

• Safety / toxicity– Choice of drugs to include in ART regimen?

• Term & preterm neonates

• Efficacy (short & longer term)– NNRTI vs PI regimen?– Role of integrase inhibitors (prophylaxis & treatment)?– Neonates with LPV-resistant HIV?

• Darunavir only approved from ≥3 yrs of age• Raltegravir only approved from ≥4 wks of age